Glaucoma is an eye disease which is an eye function disorder characterized in that aqueous humor is accumulated due to circulatory disorder of aqueous humor, an intraocular pressure is continuously increased, optic nerve is pressed, whereby it causes temporal or permanent visual field defect or low vision. The pathogenesis is said to be increase in the intraocular pressure, but there have been also known low intraocular pressure glaucoma which causes optic nerve disorder even when the intraocular pressure is in a normal value, and ocular hypertension which causes no optic nerve disorder even when the intraocular pressure is high. It is effective to lower the intraocular pressure for the treatment of the above-mentioned glaucoma and ocular hypertension. For the treatment of glaucoma and ocular hypertension, there may be mentioned, for example, drug therapy, laser therapy and surgical repair, and in the drug therapy, ophthalmic solutions which are local administration to avoid side reaction are currently the main stream.
In therapeutic agents for glaucoma or ocular hypertension presently used for clinical purposes, there are symphathetic drugs (α2 agonist, non-selective adrenergic drug, etc.), parasymphathetic drugs, sympathetic inhibitors (α1 blocker, β blocker, α1β blocker, etc.), carbonic anhydrase inhibitors, hyperosmotic agent, etc. However, in recent years, prostaglandin-like (hereinafter abbreviated to as “PG”) drugs which have potent ocular hypotensive effects and have less side effect are leapsed into the firstly selecting drugs. A function and mechanism of the drugs for reducing the intraocular pressure are to restrain formation of aqueous humor and to promote drainage of aqueous humor. In the pathway of the aqueous humor, there are a trabecular meshwork pathway and an uveoscleral pathway and a FP agonist which is a PG series drug has been reported to promote drainage of the aqueous humor through the uveoscleral pathway.
The FP agonist presently used in clinical therapy is PGF2α derivatives (Latanoprost and Isopropyl unoprostone), which is less causing allergy, and causes substantially no systemic side effect, but as a main side effect, there have been reported that it strengthens chromatosis in the iris, particularly in the iris with pale brown color, etc., and worsening in uveites, etc. Also, as the other PG receptor agonists, it has been considered that PGF1α and PGE2 derivatives are promising.
In the researches in recent years, it has been known that there exist subtypes in the PGE2 receptor each having different roles. The subtypes known at present are roughly classified into 4 types, and they are classified into EP1, EP2, EP3 and EP4, respectively. In the eye tissue of human, these 4 subtypes are expressed together (see Non-Patent Literatures 1 and 2), but each role has not yet been clarified. However, it has been clarified that the EP2 agonist has ocular hypotensive effects (see Non-Patent Literature 3), and at least a part of the ocular hypotensive effects of PGE2 is considered to be through EP2. The EP2 agonist has functions not only to promote drainage of the aqueous humor through the uveoscleral pathway, but also to promote drainage of the aqueous humor through the trabecular meshwork pathway. Moreover, the EP2 agonist does not act on melanocytes, so that the above-mentioned side effect appeared in the FP agonist can be avoided. Accordingly, it has been desired to develop an agonist which has high selectivity to the EP2 receptor in the points of medical effects and safety.
Heretofore, a number of derivatives having the PGE2 skeleton have been disclosed, and it has been known that they are effective for the treatment of various diseases (for example, asthma, bone diseases, immune diseases, etc.) (see Patent Literatures 1 to 3). Also, some EP2 agonists having no PGE2-like skeleton have been disclosed (see Patent Literatures 4 to 8), and it has been reported to shown ocular hypotensive effects (see Patent Literatures 7 and 9). However, it has never been disclosed that the sulfoneamide compounds having a specific structure of the present invention are useful for glaucoma due to ocular hypotensive effects based on the excellent EP2 receptor selectivity and potent EP2 agonistic action.    [Non-Patent Literature 1] Prostaglandins, Leukotrienes and Essential Fatty Acids, 71, 277 (2004)    [Non-Patent Literature 2] Invest. Ophthalmol. Vis. Sci., 43, 1475 (2002)    [Non-Patent Literature 3] Invest. Ophthalmol. Vis. Sci., 24, 312 (1983)    [Patent Literature 1] WO 03/37433    [Patent Literature 2] WO 02/24647    [Patent Literature 3] WO 03/74483    [Patent Literature 4] WO 98/28264    [Patent Literature 5] WO 99/19300    [Patent Literature 6] WO 2004/078169    [Patent Literature 7] WO 2008/015517    [Patent Literature 8] WO 2007/017687    [Patent Literature 9] WO 2007/027468